1. Field of the Invention
The invention relates to the fields of medicine, pharmacology, biochemistry, and cell biology. More specifically, the invention relates to the fields of dermatology and cosmetics.
2. Description of the Related Art
Melanin is a dark pigment found in plants and animals that protects against ultraviolet radiation and provides decoration in the skin, eyes, hair, and fur of animals (reviewed in Riley (1997) Int. J. Biochem. Cell Biol. 11:1235-39). Melanocytes are cells of the epidermis specialized to produce melanin, which has two forms: brown/black eumelanin and yellow/red pheomelanin. A sophisticated intercellular signaling system determines whether an individual melanocyte will produce eumelanin or pheomelanin (reviewed by Brilliant and Barsh in The Pigmentary System: Physiology and Pathophysiology, Nordlund, et al. eds., (1998) Oxford University, New York, pp. 217-229).
Melanocytes synthesize melanin inside of specialized organelles called melanosomes (reviewed by Orlow in The Pigmentary System: Physiology and Pathophysiology, Nordlund, et al., eds., (1998) Oxford University, New York, pp. 97-106). These organelles are formed by the fusion of two types of vesicles. One type of vesicle, called a premelanosome, apparently derives directly from either the smooth endoplasmic reticulum or the trans-Golgi network. The other type of vesicle derives from the trans-Golgi network. Each of these types of vesicles contributes proteins to the melanosome necessary for its function.
For many individuals of all ages, the inappropriate production or overproduction of melanin is a serious cosmetic problem. By way of example, many children develop freckles after exposure to the sun, and for individuals in middle or advanced age, chloasma, freckles, and pigmentary deposits after sunburn tend to occur or increase in frequency. In addition, these pigment deposits do not disappear quickly and are more likely to become permanent with advancing age.
A number of products have been developed to effect a decrease in skin pigmentation. One such product contains hydroquinone, a well known active substance for skin de-pigmentation (e.g., see U.S. Pat. No. 6,139,854 to Kawato et al., issued Oct. 31, 2000). However, hydroquinone can have serious side effects if applied over a long period of time. For example, the application of hydroquinone to skin may lead to permanent de-pigmentation, and thus to increased photosensitivity of the skin when exposed to ultraviolet light. For that reason, in some countries hydroquinone is only allowed to be used for skin de-pigmentation in limited concentrations, and in other countries, the product is banned completely for this application.
A variety of other substances have been proposed for the control or inhibition of skin pigmentation. Almost all of these substances work by either bleaching existing pigment or preventing new pigment synthesis by inhibiting the activity of tyrosinase, the principle rate-limiting enzyme in the production of melanin. For example, U.S. Pat. No. 6,123,959 to Jones et al., issued Sep. 26, 2000, describes the use of aqueous compositions comprising liposomes of phospholipids, and at least one competitive inhibitor of an enzyme for the synthesis of melanin, in combination with at least one noncompetitive inhibitor of an enzyme for the synthesis of melanin. U.S. Pat. No. 6,132,740 to Lan Hu, issued Oct. 17, 2000, describes the use of certain resorcinol derivatives as skin lightening agents. WO 9964025A1 by Fytokem Products Inc., published Dec. 16, 1999, describes compositions for skin lightening which contain tyrosinase inhibiting extracts from dicotyledonous plant species indigenous to Canada. U.S. Pat. No. 5,580,549 to Fukada et al., issued Dec. 3, 1996, describes an external preparation for skin lightening comprising of 2-hydroxybenzoic acid derivatives and salts thereof as inhibitors of tyrosinase. WO 9909011A1 to Ostuka Pharmaceutical Co., Ltd., published Feb. 25, 1999, describes an agent for inhibiting skin erythema and/or skin pigmentation, containing at least one carbostyril derivative and salts thereof. U.S. Pat. No. 5,214,028 to Tomita et al., issued May 25, 1993, and U.S. Pat. No. 5,389,611 to Tomita et al., issued Feb. 14, 1995, describe lactoferrin hydrolyzates for use as a tyrosinase inhibitory agents.
Despite the development of these and other compositions to lighten skin, there remains a need in the art for the development of less toxic, safer alternatives to skin bleaching and more effective and efficient methods of inhibiting melanin production. The need for new and improved methods for lightening skin is evident in view of the cosmetic industry""s estimate that the market for skin lighteners worldwide exceeds well over one billion dollars annually. Thus, there is a continuing need for the development of improved agents that limit or inhibit pigmentation in the skin.
It has surprisingly been discovered that various agents that inhibit fatty acid biosynthesis are useful for inhibiting melanin production. More specifically, it has been determined that agents capable of inhibiting fatty acid synthase (FAS) also inhibit the production of melanin in melanocytes. These discoveries have been utilized to provide the present invention, which includes methods and pharmaceutical compositions useful for decreasing skin pigmentation.
In one aspect, the invention provides a method of decreasing melanin synthesis in a melanocyte. The method comprises contacting the melanocyte with an FAS inhibitor, thereby reducing melanin synthesis in the melanocyte.
In another aspect, the invention provides a method of lightening skin, comprising contacting the skin of a patient in need thereof with a skin-lightening effective amount of an FAS inhibitor, thereby detectably reducing or inhibiting melanin synthesis and thereby lightening the skin.
The invention also provides, in another aspect, a composition for lightening skin, comprising a skin-lightening effective amount of an FAS inhibitor and a pharmaceutically acceptable carrier.
In another aspect, the present invention further provides a kit comprising a container comprising a composition comprising a skin-lightening effective amount of a compound that inhibits FAS activity. In one embodiment, the kit furthers comprises printed instructions as a label or a package insert directing the use of the pharmaceutical composition for lightening the skin.
In another aspect, the invention provides a method of making a pharmaceutical composition for lightening skin comprising combining a skin lightening effective amount of an FAS inhibitor with a pharmaceutical acceptable carrier.
In some embodiments, the FAS inhibitor is selected from the group consisting of cerulenin and a cerulenin analog, including pharmaceutically acceptable salts and solvates thereof. As used therewith, the term xe2x80x9canalogxe2x80x9d refers to a chemical compound that is structurally related to cerulenin and retains at least a measurable amount of FAS inhibitory activity. Non-limiting examples of cerulenin analogs include those described in Morisaki et al. (1992) Chem. Pharm. Bull. 40:2945-2953, Shimazawa et al. (1992) Chem. Pharm. Bull. 40:2954-2957, and U.S. Pat. No. 5,539,132 to Royer et al., issued Jul. 23, 1996. Cerulenin may be obtained commercially from Sigma (St. Louis, Mo.).
In some embodiments, the FAS inhibitor is selected from the group consisting of an xcex1-methylene-xcex3-butyrolactone and an xcex1-methylene-xcex3-butyrolactone analog, including pharmaceutically acceptable salts and solvates thereof. As used therewith, the term xe2x80x9canalogxe2x80x9d refers to a chemical compound that is structurally related to the respective xcex1-methylene-xcex3-butyrolactone and retains at least a measurable amount of FAS inhibitory activity. Non-limiting examples of xcex1-methylene-xcex3-butyrolactone analogs include those described in U.S. Pat. No. 5,981,575 to Kuhajda et al., issued Nov. 9, 1999. Alpha-methylene-xcex3-butyrolactone may be obtained commercially from Sigma (St. Louis, Mo.).
In some embodiments, the FAS inhibitor is selected from the group consisting of thiolactomycin and thiolactomycin analogs, including pharmaceutically acceptable salts and solvates thereof. As used therewith, the term xe2x80x9canalogxe2x80x9d refers to a chemical compound that is structurally related to thiolactomycin and retains at least a measurable amount of FAS inhibitory activity. Non-limiting examples of thiolactomycin analogs thereof are provided in Wang et al. (1984) Tetrahdron Lett. 25:5243-5246, Oishi et al. (1982) J. Antibiotics 35:391-395 (ATCC Strain No. 31319 disclosed therein), and Kremer et al. (2000) J. Bio. Chem. 275:16857-16864.
In other embodiments, the FAS inhibitor is triclosan or analogs thereof. Triclosan is known to inhibit enoyl-reductase of type I fatty acid synthase. In other embodiments, the inhibitors of FAS are 4-phenyl-5-phenylimino-[1,2,4] dithiazolidin-3-one) or 5-chloro-4-phenyl-[1,2]-dithiol-3-one).